Druthers, Grim

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The NIH panel convened late last November to develop new state-of-the-art guidelines for the treatment of HIV infection included a series of provocative (some would say alarming) presentations regarding resistance considerations in the choice of antiretroviral combination regimens. TAG's indefatigable scribe and provocateur in his own right, Mark Harrington, provided this transcript of the cross-fire which featured, among others: Merck's Emilio Emini, Tufts University's John Coffin, University of Montréal's Mark Wainberg, Roche's Noel Roberts, the CDC's Harold Jaffe, Chiron's David Chernoff, the ACTG's Robert ("Chip") Schooley and John Mellors, as well as fellow treatment activist Dawn Averitt-Doherty of Atlanta-based Woman's Information Service and Exchange (WISE).

Mark Wainberg presented interesting resistance data from BI 1046 (the INCAS study of AZT+ddI+nevirapine (NVP) vs. AZT+ddI vs. AZT+NVP in treatment naïve individuals with CD4 cell counts 200-600), analyzing compliance as defined by any patient who did not miss more than 28 days of any therapy. On triple drug therapy, viral load was reduced by 1.5 logs at 23 weeks. Patients non-compliant to ddI rapidly became resistant to nevirapine. At twelve months, even some of those who were compliant developed NVP resistance, although in most patients on triple therapy (87%) it was difficult to culture virus. At twelve months, virus could not be cultured from any patient whose viral load was beneath the limit of detection (LOD). When treatment reduces viral load below LOD, virus culturable from peripheral blood mononuclear cells (PBMCs) at six months is wild-type. When treatment fails, virus culturable from PBMCs as six months is NVP resistant, but not as frequently (or as highly so) as in patients receiving only AZT and NVP.

Coffin: Both studies (BI 1046 and the Merck 035 study, presented earlier that day) raise the question of whether there's a rationale to include AZT anymore. It makes no difference between experienced and naïve patients. NVP and AZT didn't push the virus very hard.

Wainberg: Combinations without AZT should be looked at-they're tantalizing.

Emini: The combination of d4T and 3TC should be looked at.

Coffin: We need to study the fitness of various mutants in the absence of therapy. Some mutants will have a high cost to fitness, and will be infrequent; while others may have a low cost and may be more common. There may be an evolutionary bottleneck early in disease before which such pre-existent mutants are rare, but six months into infection-or after a year-you've lost that advantage.

Harrington: It seems to me there are two ways to avoid the development of resistance here: one is to suppress maximally with potent antiretroviral regimens. The other is to wait to begin therapy until it's necessary to prevent irreversible immunologic damage. If the only point at which to throttle the virus from an evolutionary standpoint [to limit the pool of pre-existing drug-resistant viral mutants] is in the first 6-12 months of infection, this has little relevance to most chronically-infected patients who, given the limitations of our arsenal, might be better of waiting for a clear need to emerge.

Roche's Noel Roberts presented cross-resistance data on clinical isolates which had been presented at the Birmingham conference, suggesting that HIV that has developed resistance to any of the three licensed protease inhibitors is likely to be resistant to the other ones (licensed and unlicensed) as well, and that resistance to IDV (currently the most widely prescribed protease inhibitor) appeared to confer 60% cross-resistance to SQV, 80% cross-resistance to the Vertex compound (141WU94) and 100% cross-resistance to RTV and NFV! University of North Caro-lina's Robert Swanstrom took it a step further and looked at HIV that had become doubly protease resistant (to SQV+RTV, RTV+IDV and SQV+IDV). In his in vitro experiments, HIV that was doubly resistant to IDV+RTV was 400-fold less susceptible to SQV. And HIV with dual resistance to SQV+RTV was 60-fold less sensitive to IDV. So the implication for people failing SQV, IDV or RTV appear grim-at least from this data.

Schooley: We need to be pretty careful and do in vivo studies of switching people from saquinavir to other protease inhibitors and vice versa.

Roberts: That study is underway.

Chernoff: In these trials, drug is continued post-failure, unlike in clinical practice. [This is not true; many doctors continue patients on therapy post-failure. What else can they do? There are no clinical practice guidelines out there, and many people have failed all available drugs.]

Mellors: It troubles me to hear a comparison of the frequency of resistance without controlling for the potency of the various regimens. The two variables are related-viral turnover and the selection process imposed by more or less potent regimens.

Jaffe: If resistant mutations are associated with a selective disadvantage will they disappear after treatment is removed?

Emini: Two patients who stopped taking indinavir (one after taking low-dose, then full-dose) had a reversion to wild-type within 4-5 months post-cessation. One restarted treatment at full-dose idv, and within three weeks we isolated idv-resistant virus. This is why we say the virus is "genetically unforgiving."

During the coffee break, I joined three activists outside to share nicotine and despair. What was the point of quitting smoking if we were still all passengers on the speeding train heading for the cliff? The Birmingham resistance data were wrenching. Our fears of multiple cross-resistance, from November 1995's 3TC and saquinavir FDA approval hearings, reared their ugly heads. Several months of post-Vancouver euphoria crumbled in a moment as it became clear that many of those who developed resistance to ritonavir and idv-as thousands clearly would-might have no protease inhibiting options ahead of them. Today's resistance news made for a toxic cocktail. As I left the auditorium I bumped into Emilio Emini.

Harrington: So what do you do if you fail Crixivan?

Emini: [sighs] We don't know what to do.

Harrington: Take two new nucleosides and nevirapine?

Emini: Yeah. And pray.

No one had yet assessed the healing effects of prayer on viral load. This was what we'd come to. I rushed into the lobby of the Interior Department and ran into a colleague, who was wild with fear and disappointment.

Averitt: Why don't you wait until you get your latest numbers and see what your resistance profile is?

AC: I'm going to go outside and have a nervous breakdown.

We went outside. It was frigid, and fragile snowflakes swirled around in the wind. Sometimes the gap between how the researchers felt and how we felt became an abyss. They were excited about the endless possibilities opened up by the research advances of 1996; we were terrified about the limited treatment options facing people who had exhausted most of the current arsenal of antiretroviral therapy. What to do with those whose viral load refused to go undetectable? What to do with those who added a protease inhibitor to a failing two-drug regimen and appeared doomed to develop resistance, most of it-especially with ritonavir and idv-cross-resistant to all other protease inhibitors? What to do with those who jumped aboard last year's bandwagon, AZT+3TC, and now appeared likely to have developed 3TC resistance and, with it, cross-resistance to ddI, ddC and possibly 1592? The Chinese menu approach to antiretroviral treatment sud denly looked much less appetizing, and much less nourishing.

Dawn and I went upstairs where the committee was having a working lunch, discussing process. Many members questioned the existence of two committees. Why have one committee setting up principles (NIH) and one setting up practice guidelines (PHS)? Wasn't this a recipe for bureaucratic confusion-and delay? How could we disseminate principles of HIV therapy without making practice guidelines? What if the principles contradicted the data? Considering what we had just seen, doing something fast seemed imperative.

On the other hand, many of the researchers present did not share the activist sense that we were facing a crisis that, if handled improperly, might make things worse than before. This was not the prevailing view propounded by gun-happy virologists, drug-happy pharmaceutical companies, media captivated by a surprising good-news story and many people with HIV still struggling to absorb the complex developments of 1996. Just that week, back-to-back articles in The Wall Street Journal and The New York Times Magazine, both written by HIV-infected journalists, declared that the epidemic was virtually over. We were staring into the precipice while others were still climbing the hill.